The present invention relates to a composition for the prevention or treatment of diseases associated with angiogenesis, and in detail, to a composition comprising the extract of Cnidium officinale Makino (C. officinale) or the fraction thereof for the prevention or treatment of diseases associated with angiogenesis.
Angiogenesis is the process of generating new capillary blood vessels. Neovascularization is tightly regulated, and its activation occurs in embryogenic development, tissue remodeling, wound healing, and periodic cycles of corpus luteum development (Folkman and Cortran, Int. Rev. Exp. Pathol., 16, pp 207-248, 1976).
For the case of adult, the endothelial cells very slowly proliferate and rarely differentiate as compared with other types of cells in the body.
In general, the process of angiogenesis consists of proteolytic degradation of endothelial basement membrane induced by angiogenic factors; movement and proliferation of endothelial cells; tube formation induced by differentiation of endothelial cells; rearrangement of blood vessels; and formation of new capillary blood vessels.
Some diseases are developed by the failure of regulation of angiogenesis and the pathological growth of blood vessels. Cardiovascular diseases such as angioma, angiofibrioma, vascular deformity, atherosclerosis, synechia and edemic sclerosis; and ophthalmologic diseases such as neovascularization after cornea implantation, neovascular glaucoma, diabetic retinopathy, angiogenic corneal disease, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasias, and granular conjunctivitis are diseases related to angiogenesis. Chronic inflammatory diseases such as arthritis; dermatological disease such as psoriasis, telangiectasis, pyogenic granuloma, seborrheic dermatitis and acne; and Alzheimer's disease, obesity, and the growth and metastasis of cancer are also angiogenesis-dependent diseases (D'Amato R J and Adamis A P, Ophthalmol., 102, pp 1261-1262, 1995; Arbiser J L. J. Am. Acad. Derm., 34(3), pp 486-497, 1996; O'Brien K D et al. Circulation, 93(4), pp 672-682, 1996; Hanahan D and Folkman J, Cell, 86, pp 353-364, 1996).
In particular, angiogenesis is essential to growth and metastasis of cancer. New blood vessels not only provide nutrients and oxygen to fast-growing cancer cells, but also give ways of entering the blood stream resulting in metastasis (Folkman and Tyler, Cancer Invasion and Metastasis, Biological mechanisms and Theraphy (S. B. Day ed.) Raven press, New York, pp 94-103, 1977; Polverini P J, Critical Reviews in Oral Biology, 6(3), pp 230-247, 1995). Currently, a large variety of chemotherapies and immunotherapies are applied in the treatment of cancer, but the efficacy of these therapies is limited and nothing can successfully extend the life of cancer patients due to the lack of anti-metastasis effects.
Arthritis, a well-known inflammatory disease, is initiated as an autoimmune disease. During the progression of inflammation, the growth of vascular endothelial cell in synovial cavity is activated by cytokines. The cartilage in articulation is finally destroyed by the formation of articular lamina leak (Kocb A E et al., Arth. Rheum., 29, pp 471-479, 1986; Stupack D G et al., Braz. J. Med. Biol. Rcs., 32, pp 578-581, 1999; Koch A E, Arth. Rheum., 41, pp 951-962, 1998).
Many people are losing their eyesight all over the world because of various ocular diseases. Many patients became blind due to the infiltration of capillary blood cells into the vitreous humor (Jeffrey M I and Takayuki A, J. Clin. Invest., 103, pp 1231-1236, 1999). Therefore, the inhibition of angiogenesis is the basic therapeutic modality for these diseases.
Psoriasis is caused by extremely active proliferation of skin cells. Fast-growing cells require sufficient blood supply, and angiogenesis is abnormally induced in psoriasis (Folkman J., J. Invest. Dermatol., 59, pp 40-48, 1972).
For the case of obesity, adipose tissue mass can be regulated by its vasculature, and the treatment of angiogenesis inhibiter decreases both body weight and adipose tissue mass in dose-dependent manner (Rupnick M A et al., Proc. Natl. Acad. Sci. U.S.A., 90(16), pp 10730-10735, 2002).
In Alzheimer's diseases, it was found that large populations of endothelial cells are activated by angiogenesis due to brain hypoxia and inflammation, and the brain endothelium secretes the precursor substrate for beta-amyloid plaque and a neurotoxin peptide. Alzheimer's disease can be treated and prevented by angiogenesis inhibitors, which are specific to abnormal brain endothelial cells (Vagnucci A H et al., Lancet, 361, pp 605-608, 2003).
Since angiogenesis is closely related to initiation and progression of many diseases, many efforts have been made toward the development of angiogenesis inhibitors in order to prevent or treat these diseases. Since these inhibitors need to be administered for a long time, desirable inhibitors should not have toxic or adverse effects with good patient compliance.
C. officinale is a plant in Umbelliferae. In folk medicine, its dried root has been used for headache, infertility, menstrual disorder, anemia, and tonic. Chemical compositions of C. officinale consist of phthalide compounds such as cnidilide, neocnidilide, ligustilide, butylphthalide, and senkyunolide (Fuzita M. and Kobayashi M., Chem. Pharm. Bull., 35(4), pp 1427-1433, 1987).
The present inventors have found that the extracts of C. officinale and the fractions thereof have inhibitory effects on angiogenesis, and they have purified effective ingredients from extracts of C. officinale that can inhibit angiogenesis.